Abstract. The goal of Project 4 is to delineate the complex interactions between genetic ancestry and environmental factors in the rate of progression and severity of renal involvement and organ damage associated with systemic lupus erythematosus (SLE). The hypothesis is that SLE patients with a greater percentage of African or Amerindian ancestry genes both alone and in combination with environmental factors, including low individual- and group-level SES constructs, have more severe and rapidly progressive SLE as defined by several longitudinal clinical and soluble biomarker indices. To address this hypothesis, we intend to (1) use panels of established ancestry informative markers (AIMs) to estimate the extent of individual admixture separately among European American (EA), African American (AA), Hispanic [from Texas (H-TX), Puerto Rico (H-PR) and Mexico (H-M)] SLE patients with and without renal involvement and organ damage after controlling for confounding factors; (2) determine the extent to which the estimates of individual admixture among these groups relate to the time to indices of renal involvement and organ damage; and (3) determine the extent to which individual- and group-level SES constructs modify the effect (additive joint effects and epistasis) of individual admixture on the presence/absence, time to and severity of renal involvement and organ damage among patients with SLE. Using the expanded PROFILE cohort of current and newly enrolled SLE patients meeting 4 of 11 ACR criteria from the participating 8 study sites in the continental US, Puerto Rico and Mexico, we intend to exploit targeted independent and joint contributions of genetic ancestry, using well-characterized AIMs, and environmental (SES) factors with the tempo of SLE progression. The pooled study population will represent the largest multi-ethnic population to date of SLE patients, which will allow for a comprehensive evaluation of gene and environmental influences that are dimorphic by race/ethnicity. This approach offers the best opportunity to rapidly exploit these relationships and to provide novel insight into the course and outcome of SLE. Results from this longitudinal investigation will address key questions for understanding the relative contributions of environmental factors and genetic ancestry that may account for the disparate trends of SLE-related morbidities, severity and progression that is observed among populations of African and Hispanic ancestries. Relationship of Project with Overall PPG Priorities. The proposed research plan is designed to examine the interactions between genetic ancestry markers and environmental factors in the rate of progression and severity of SLE. This research plan will (1) maximize synergy between all four PPG projects as well as the Administrative and Genetic Epidemiology and Biostatistics Cores thereby facilitating a rigorous evaluation of our stated specific aims in a time and cost-effective manner, (2) increase collaboration between partner institutions, (3) foster the continued development of an effective Rheumatic Diseases Research Program, (4) enhance research efforts toward SLE-related health disparities and (5) provide novel insight to the genetic etiology of this enigmatic autoimmune phenotype that is disproportionately more frequent and severe among ethnic minority populations. In this capacity, this investigation may be used to ultimately narrow the gap in SLE morbidity and mortality that is disparately observed between African Americans and Hispanic populations.